Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

The ATTACC, ACTIV-4a, and REMAP-CAP Investigators; Anand Kumar; Shailesh Bihari; Allen C. Cheng; Mark Fitzgerald

doi:10.1056/NEJMoa2105911

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

The ATTACC, ACTIV-4a, and REMAP-CAP Investigators, Anand Kumar, Shailesh Bihari, Allen C. Cheng, Mark Fitzgerald

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

752 Citations (Scopus)

Abstract

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.

RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.

CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.

Original language	English
Pages (from-to)	790-802
Number of pages	13
Journal	New England Journal of Medicine
Volume	385
Issue number	9
DOIs	https://doi.org/10.1056/NEJMoa2105911
Publication status	Published - 26 Aug 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

anticoagulation/thromboembolism (pulmonary/critical care)
anticoagulation/thromboembolism (cardiology)
coronavirus

Access to Document

10.1056/NEJMoa2105911Licence: In Copyright

Cite this

@article{d081a76bcc98436c830662e7be467080,

title = "Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19",

abstract = "BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.",

keywords = "anticoagulation/thromboembolism (pulmonary/critical care), anticoagulation/thromboembolism (cardiology), coronavirus",

author = "{The ATTACC, ACTIV-4a, and REMAP-CAP Investigators} and Lawler, {Patrick R.} and Goligher, {Ewan C.} and Berger, {Jeffrey S.} and Neal, {Matthew D.} and McVerry, {Bryan J.} and Nicolau, {Jose C.} and Gong, {Michelle N.} and Marc Carrier and Rosenson, {Robert S.} and Reynolds, {Harmony R.} and Turgeon, {Alexis F.} and Jorge Escobedo and Huang, {David T.} and Bradbury, {Charlotte A.} and Houston, {Brett L.} and Kornblith, {Lucy Z.} and Anand Kumar and Kahn, {Susan R.} and Mary Cushman and Zoe McQuilten and Slutsky, {Arthur S.} and Kim, {Keri S.} and Gordon, {Anthony C.} and Kirwan, {Bridget Anne} and Brooks, {Maria M.} and Higgins, {Alisa M.} and Lewis, {Roger J.} and Elizabeth Lorenzi and Berry, {Scott M.} and Berry, {Lindsay R.} and Angus, {Derek C.} and McArthur, {Colin J.} and Webb, {Steven A.} and Farkouh, {Michael E.} and Hochman, {Judith S.} and Ryan Zarychanski and Aday, {Aaron W.} and Farah Al-Beidh and Djillali Annane and Arabi, {Yaseen M.} and Diptesh Aryal and Kreuziger, {Lisa Baumann} and Abi Beane and Zahra Bhimani and Shailesh Bihari and Billett, {Henny H.} and Lindsay Bond and Marc Bonten and Frank Brunkhorst and Meredith Buxton and Adrian Buzgau and Castellucci, {Lana A.} and Sweta Chekuri and Chen, {Jen Ting} and Cheng, {Allen C.} and Tamta Chkhikvadze and Benjamin Coiffard and Costantini, {Todd W.} and {de Brouwer}, Sophie and Derde, {Lennie P.G.} and Detry, {Michelle A.} and Abhijit Duggal and Vladim{\'i}r D{\v z}av{\'i}k and Effron, {Mark B.} and Estcourt, {Lise J.} and Everett, {Brendan M.} and Fergusson, {Dean A.} and Mark Fitzgerald and Fowler, {Robert A.} and Galanaud, {Jean P.} and Galen, {Benjamin T.} and Sheetal Gandotra and Sebastian Garc{\'i}a-Madrona and Girard, {Timothy D.} and Godoy, {Lucas C.} and Goodman, {Andrew L.} and Herman Goossens and Cameron Green and Greenstein, {Yonatan Y.} and Gross, {Peter L.} and Hamburg, {Naomi M.} and Rashan Haniffa and George Hanna and Nicholas Hanna and Hegde, {Sheila M.} and Hendrickson, {Carolyn M.} and Hite, {R. Duncan} and Hindenburg, {Alexander A.} and Hope, {Aluko A.} and Horowitz, {James M.} and Horvat, {Christopher M.} and Kristin Hudock and Hunt, {Beverley J.} and Mansoor Husain and Hyzy, {Robert C.} and Iyer, {Vivek N.} and Jacobson, {Jeffrey R.} and Devachandran Jayakumar and Keller, {Norma M.} and Akram Khan and Yuri Kim and Kindzelski, {Andrei L.} and King, {Andrew J.} and Knudson, {M. Margaret} and Kornblith, {Aaron E.} and Vidya Krishnan and Kutcher, {Matthew E.} and Laffan, {Michael A.} and Francois Lamontagne and {Le Gal}, Gr{\'e}goire and Leeper, {Christine M.} and Leifer, {Eric S.} and George Lim and Lima, {Felipe Gallego} and Kelsey Linstrum and Edward Litton and Jose Lopez-Sendon and {Lopez-Sendon Moreno}, {Jose L.} and Lother, {Sylvain A.} and Saurabh Malhotra and Miguel Marcos and Marinez, {Andr{\'e}a Saud} and Marshall, {John C.} and Nicole Marten and Matthay, {Michael A.} and McAuley, {Daniel F.} and McDonald, {Emily G.} and Anna McGlothlin and McGuinness, {Shay P.} and Saskia Middeldorp and Montgomery, {Stephanie K.} and Moore, {Steven C.} and Guerrero, {Raquel Morillo} and Mouncey, {Paul R.} and Srinivas Murthy and Nair, {Girish B.} and Rahul Nair and Nichol, {Alistair D.} and Brenda Nunez-Garcia and Ambarish Pandey and Park, {Pauline K.} and Parke, {Rachael L.} and Parker, {Jane C.} and Sam Parnia and Paul, {Jonathan D.} and {P{\'e}rez Gonz{\'a}lez}, {Yessica S.} and Mauricio Pompilio and Prekker, {Matthew E.} and Quigley, {John G.} and Rost, {Natalia S.} and Kathryn Rowan and Santos, {Fernanda O.} and Marlene Santos and Santos, {Mayler Olombrada} and Lewis Satterwhite and Saunders, {Christina T.} and Schutgens, {Roger E.G.} and Seymour, {Christopher W.} and Siegal, {Deborah M.} and Silva, {Delcio G.} and Manu Shankar-Hari and Sheehan, {John P.} and Singhal, {Aneesh B.} and Dayna Solvason and Stanworth, {Simon J.} and Tobias Tritschler and Turner, {Anne M.} and {van Bentum-Puijk}, Wilma and {van de Veerdonk}, {Frank L.} and {van Diepen}, Sean and Gloria Vazquez-Grande and Lana Wahid and Vanessa Wareham and Wells, {Bryan J.} and Widmer, {R. Jay} and Wilson, {Jennifer G.} and Eugene Yuriditsky and Zampieri, {Fernando G.}",

year = "2021",

month = aug,

day = "26",

doi = "10.1056/NEJMoa2105911",

language = "English",

volume = "385",

pages = "790--802",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "9",

}

TY - JOUR

T1 - Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

AU - The ATTACC, ACTIV-4a, and REMAP-CAP Investigators

AU - Lawler, Patrick R.

AU - Goligher, Ewan C.

AU - Berger, Jeffrey S.

AU - Neal, Matthew D.

AU - McVerry, Bryan J.

AU - Nicolau, Jose C.

AU - Gong, Michelle N.

AU - Carrier, Marc

AU - Rosenson, Robert S.

AU - Reynolds, Harmony R.

AU - Turgeon, Alexis F.

AU - Escobedo, Jorge

AU - Huang, David T.

AU - Bradbury, Charlotte A.

AU - Houston, Brett L.

AU - Kornblith, Lucy Z.

AU - Kumar, Anand

AU - Kahn, Susan R.

AU - Cushman, Mary

AU - McQuilten, Zoe

AU - Slutsky, Arthur S.

AU - Kim, Keri S.

AU - Gordon, Anthony C.

AU - Kirwan, Bridget Anne

AU - Brooks, Maria M.

AU - Higgins, Alisa M.

AU - Lewis, Roger J.

AU - Lorenzi, Elizabeth

AU - Berry, Scott M.

AU - Berry, Lindsay R.

AU - Angus, Derek C.

AU - McArthur, Colin J.

AU - Webb, Steven A.

AU - Farkouh, Michael E.

AU - Hochman, Judith S.

AU - Zarychanski, Ryan

AU - Aday, Aaron W.

AU - Al-Beidh, Farah

AU - Annane, Djillali

AU - Arabi, Yaseen M.

AU - Aryal, Diptesh

AU - Kreuziger, Lisa Baumann

AU - Beane, Abi

AU - Bhimani, Zahra

AU - Bihari, Shailesh

AU - Billett, Henny H.

AU - Bond, Lindsay

AU - Bonten, Marc

AU - Brunkhorst, Frank

AU - Buxton, Meredith

AU - Buzgau, Adrian

AU - Castellucci, Lana A.

AU - Chekuri, Sweta

AU - Chen, Jen Ting

AU - Cheng, Allen C.

AU - Chkhikvadze, Tamta

AU - Coiffard, Benjamin

AU - Costantini, Todd W.

AU - de Brouwer, Sophie

AU - Derde, Lennie P.G.

AU - Detry, Michelle A.

AU - Duggal, Abhijit

AU - Džavík, Vladimír

AU - Effron, Mark B.

AU - Estcourt, Lise J.

AU - Everett, Brendan M.

AU - Fergusson, Dean A.

AU - Fitzgerald, Mark

AU - Fowler, Robert A.

AU - Galanaud, Jean P.

AU - Galen, Benjamin T.

AU - Gandotra, Sheetal

AU - García-Madrona, Sebastian

AU - Girard, Timothy D.

AU - Godoy, Lucas C.

AU - Goodman, Andrew L.

AU - Goossens, Herman

AU - Green, Cameron

AU - Greenstein, Yonatan Y.

AU - Gross, Peter L.

AU - Hamburg, Naomi M.

AU - Haniffa, Rashan

AU - Hanna, George

AU - Hanna, Nicholas

AU - Hegde, Sheila M.

AU - Hendrickson, Carolyn M.

AU - Hite, R. Duncan

AU - Hindenburg, Alexander A.

AU - Hope, Aluko A.

AU - Horowitz, James M.

AU - Horvat, Christopher M.

AU - Hudock, Kristin

AU - Hunt, Beverley J.

AU - Husain, Mansoor

AU - Hyzy, Robert C.

AU - Iyer, Vivek N.

AU - Jacobson, Jeffrey R.

AU - Jayakumar, Devachandran

AU - Keller, Norma M.

AU - Khan, Akram

AU - Kim, Yuri

AU - Kindzelski, Andrei L.

AU - King, Andrew J.

AU - Knudson, M. Margaret

AU - Kornblith, Aaron E.

AU - Krishnan, Vidya

AU - Kutcher, Matthew E.

AU - Laffan, Michael A.

AU - Lamontagne, Francois

AU - Le Gal, Grégoire

AU - Leeper, Christine M.

AU - Leifer, Eric S.

AU - Lim, George

AU - Lima, Felipe Gallego

AU - Linstrum, Kelsey

AU - Litton, Edward

AU - Lopez-Sendon, Jose

AU - Lopez-Sendon Moreno, Jose L.

AU - Lother, Sylvain A.

AU - Malhotra, Saurabh

AU - Marcos, Miguel

AU - Marinez, Andréa Saud

AU - Marshall, John C.

AU - Marten, Nicole

AU - Matthay, Michael A.

AU - McAuley, Daniel F.

AU - McDonald, Emily G.

AU - McGlothlin, Anna

AU - McGuinness, Shay P.

AU - Middeldorp, Saskia

AU - Montgomery, Stephanie K.

AU - Moore, Steven C.

AU - Guerrero, Raquel Morillo

AU - Mouncey, Paul R.

AU - Murthy, Srinivas

AU - Nair, Girish B.

AU - Nair, Rahul

AU - Nichol, Alistair D.

AU - Nunez-Garcia, Brenda

AU - Pandey, Ambarish

AU - Park, Pauline K.

AU - Parke, Rachael L.

AU - Parker, Jane C.

AU - Parnia, Sam

AU - Paul, Jonathan D.

AU - Pérez González, Yessica S.

AU - Pompilio, Mauricio

AU - Prekker, Matthew E.

AU - Quigley, John G.

AU - Rost, Natalia S.

AU - Rowan, Kathryn

AU - Santos, Fernanda O.

AU - Santos, Marlene

AU - Santos, Mayler Olombrada

AU - Satterwhite, Lewis

AU - Saunders, Christina T.

AU - Schutgens, Roger E.G.

AU - Seymour, Christopher W.

AU - Siegal, Deborah M.

AU - Silva, Delcio G.

AU - Shankar-Hari, Manu

AU - Sheehan, John P.

AU - Singhal, Aneesh B.

AU - Solvason, Dayna

AU - Stanworth, Simon J.

AU - Tritschler, Tobias

AU - Turner, Anne M.

AU - van Bentum-Puijk, Wilma

AU - van de Veerdonk, Frank L.

AU - van Diepen, Sean

AU - Vazquez-Grande, Gloria

AU - Wahid, Lana

AU - Wareham, Vanessa

AU - Wells, Bryan J.

AU - Widmer, R. Jay

AU - Wilson, Jennifer G.

AU - Yuriditsky, Eugene

AU - Zampieri, Fernando G.

PY - 2021/8/26

Y1 - 2021/8/26

N2 - BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.

AB - BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.

KW - anticoagulation/thromboembolism (pulmonary/critical care)

KW - anticoagulation/thromboembolism (cardiology)

KW - coronavirus

UR - http://www.scopus.com/inward/record.url?scp=85114018681&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/NHMRC/1101719

UR - http://purl.org/au-research/grants/NHMRC/1116530

U2 - 10.1056/NEJMoa2105911

DO - 10.1056/NEJMoa2105911

M3 - Article

C2 - 34351721

AN - SCOPUS:85114018681

SN - 0028-4793

VL - 385

SP - 790

EP - 802

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 9

ER -

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this